The essence of this SCOR proposal encompasses the development of a unified research effort to understand the processes that influence CI- secretion in airway epithelia, and the role of CI- secretory pathways in CF pathogenesis. The thrust of each component is to focus on a well-defined and integrated set of problems that range from the elucidation and correction of translational defects in CFTR, to novel features of CFTR regulation in vitro and in vivo, means by which alternative Cl-secretory pathways may genetically modify the CF phenotype, ways in which other membrane proteins (e.g., p11, annexins) govern CFTR regulation, and features of human pulmonary physiology that influence disease progression. The present projects in this SCOR include four research program leaders and two core directors with long-standing dedication to CF research. The four projects and two cores described in this SCOR proposal are not only synergistic but in fact require each other in order to succeed. These include: "CFTR Regulation by the p11-annexin II Complex," K.L. Kirk, Ph.D., "Alternate Cl- Secretory Pathways in Cystic Fibrosis, D.J. Benos, Ph.D., "Pharmacological Suppression of CFTR Stop Mutations, D.M. Bedwell, Ph.D., "Mouse Genetics Core," R. Rozmahel, Ph.D., "Assay Core," E.M. Schwiebert. Because all projects within the SCOR share the same goal, they are interactive and mutually reinforcing. In summary, we propose an aggressive, multi-pronged attack aimed at developing a comprehensive and mechanistic understanding of CI- secretion in CF pathophysiology.